Preparation of polycyclic ethers

ABSTRACT

Process for the preparation of polycyclic ethers of formula ##STR1## wherein X represents --(CH 2 ) n  --, index n stands for integer 0 or 1, symbol R 4  designates a hydrogen atom or a methyl radical, symbols R 1  and R 2 , identical or different, represent each a hydrogen atom or a lower alkyl radical from C 1  to C 3  and R designates either a C 1  to C 6  linear or branched alkyl radical, or a substituted or unsubstituted alkenyl radical having 2 or 3 carbon atoms in the main chain, said alkenyl radical forming a ring such as indicated by the dotted line, which process comprises the cyclization by means of an acidic agent of an unsaturated compound: 
     a) of formula ##STR2##  having a double bond in one of the positions indicated by the dotted lines, and wherein index m defines an integer number equal to 1 or 2, symbol R 3  stands for a hydrogen atom or a protecting group of the hydroxyl function bound to the oxygen atom and able to dissociate itself from the latter under the reaction conditions, the wavy line represents a C--C bond of cis or trans configuration and index n and symbols R, R 2  and R 4  are defined as above; or 
     b) of formula ##STR3##  wherein symbols R 2 , R 3  and R 4 , index n and the wavy line are defined as above; or 
     c) of formula ##STR4##  wherein symbols, R 2 , R 3  and R 4 , index n and the wavy line are defined as above. 
     Some of the compounds (I) are novel and can be used in the perfume industry.

This is a division of application Ser. No. 07/539,113, filed Jun. 15,1990, U.S. Pat. No. 5,077,417.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for the preparation ofpolycyclic ethers of formula ##STR5## wherein X represents --(CH₂)_(n)--, index n stands for integer 0 or 1, symbol R⁴ designates a hydrogenatom or a methyl radical, symbols R¹ and R², identical or different,represent each a hydrogen atom or a lower alkyl radical from C₁ to C₃and R designates either a C₁ to C₆ linear or branched alkyl radical, ora substituted or unsubstituted alkenyl radical having 2 or 3 carbonatoms in the main chain, said alkenyl radical forming a ring such asindicated by the dotted line, which process comprises the cyclization bymeans of an acidic agent of an unsaturated compound:

a) of formula ##STR6## having a double bond in one of the positionsindicated by the dotted lines, and wherein index m defines an integernumber equal to 1 or 2, symbol R³ stands for a hydrogen atom or aprotecting group of the hydroxyl function bound to the oxygen atom andable to dissociate itself from the latter under the reaction conditions,the wavy line represents a C--C bond of cis or trans configuration andindex n and symbols R, R² and R⁴ are defined as above; or

b) of formula ##STR7## wherein symbols R², R³ and R⁴, index n and thewavy line are defined as above; or

c) of formula ##STR8## wherein symbols R², R³ and R⁴, index n and thewavy line are defined as above.

The invention also relates to novel compounds of formula (I) wherein R²stands for a methyl radical and to their use as perfuming ingredients inthe preparation of perfuming compositions and perfumed articles.

Another object of the present invention is an isomeric mixture ofpolycyclic ethers of formula ##STR9## containing a preponderant amountof isomer3aα,5aβ,9aα,9aβ-dodecahydro-3a,6,6,9a-tetramethyl-naphtho[2,1-b]furan.

BACKGROUND OF THE INVENTION

In commercial preparations, the compound of formula ##STR10## or3aα,5aβ,9aα,9bβ-dodecahydro-3a,6,6,9a-tetramethyl-naphtho[2,1-b]furan,known under the commercial name of AMBROX® (origin: Firmenich SA,Geneva), is often accompanied by variable amounts of itsdiastereoisomers, amongst which epi-AMBROX and iso-AMBROX.

Ever since its discovery [see Helv. Chim. Acta 33, 1251 (1950)], therehave been many reported processes for the preparation of this compound.Said processes are generally based on a reaction of oxidativedegradation of terpenes such a (-)-sclareol or (+)-manol, or on the useof ambriene as starting material [G. Ohloff in "Fragrance Chemistry",ed. Ernst T. Theimer, p. 545 and following, Academic Press (1982)]. Allthese materials are of natural origin and therefore their availabilityand quality are dependent on variable climatic conditions and particularsocio-economical factors.

In addition, since they are extracted from natural sources with modestyields, they are available at a price which renders their use on anindustrial scale uneconomical.

A process disclosing the cyclization of homofarnesic acid intonorambreinolide, followed by the reduction of the obtained lactones andthe cyclization of the resulting diol to provide the desired furanderivative, has been reported in European Patent no. 107 857. Accordingto this process, the cyclization of homofarnesic acid is achieved bymeans of SnCl₄.

A similar synthetic approach had been suggested by A. Saito et al.[Chemistry Letters 757 (1981)]. These authors had realized thecyclization of trans-β-monocyclohomofarnesic acid using same SnCl₄ ascyclization agent. The two cited documents, incidentally, represent anextension of the work done by G. Lucius on the cyclization ofhomofarnesic acid [Angew. Chem. 68, 247 (1956); Arc. Pharm. 291, 57(1958) and Chem. Ber. 93, 2663 (1960)].

Recently, S. Neumann and H. Simon [Biol. Chem. Hoppe-Seiler 367 (8), 723(1986)] described the formation of3a,6,6,9a-tetramethyl-perhydronaphtho[2,1-b]furan by an enzymaticcyclization of homofarnesol or ofhomofarnesyl-(1,5,9-trimethyl-4,8-decadienyl)ether. However, for themoment, such a process has only a purely academic interest, due to theparticular nature of the reagents employed, as well as to the observedyields and conversion rates.

The special contribution that AMBROX makes to the perfume industry andthe need to have it at a lower market price prompted us to re-examinethe available processes for its synthesis. The present invention bringsa novel and original solution to this problem.

THE INVENTION

One object of the present invention is to provide a process for thepreparation of polycyclic ethers of formula ##STR11## wherein Xrepresents --(CH₂)_(n) --, index n stands for integer 0 or 1, symbol R⁴designates a hydrogen atom or a methyl radical, symbols R¹ and R²,identical or different, represent each a hydrogen atom or a lower alkylradical from C₁ to C₃ and R designates either a C₁ to C₆ linear orbranched alkyl radical, or a substituted or unsubstituted alkenylradical having 2 or 3 carbon atoms in the main chain, said alkenylradical forming a ring such as indicated by the dotted line, whichprocess comprises the cyclization by means of an acidic agent of anunsaturated compound

a) of formula ##STR12## having a double bond in one of the positionsindicated by the dotted lines, and wherein index m defines an integernumber equal to 1 or 2, symbol R³ stands for a hydrogen atom or aprotecting group of the hydroxyl function bound to the oxygen atom andable to dissociate itself from the latter under the reaction conditions,the wavy line represents a C--C bond of cis or trans configuration andindex n and symbols R, R² and R⁴ are defined as above; or

b) of formula ##STR13## wherein symbols R², R³ and R⁴, index n and thewavy line are defined as above; or

c) of formula ##STR14## wherein symbols R², R³ and R⁴, index n and thewavy line are defined as above.

As indicated above, symbol R³ represents a hydrogen atom or a protectinggroup of the hydroxyl function bound to the oxygen atom and able todissociate from it under the reaction conditions. In this case, such aprotecting group is a radical having a bond with the oxygen atom whichis labile under the acidic medium in which the cyclization takes place.Examples of radicals capable of having this function are well-known inthe art. In particular, and as an example, one can cite the radicals ofthe tetrahydropyranyl, trialkylsilyl, tert-butyl or acyl type.

As acidic cyclization agent, a mineral or organic protonic acid can beused, for example, a carboxylic or sulphonic acid, or yet a Lewis typeacid. Amongst the mineral acids, one can cite the phosphoric, sulphuricand perchloric acids, the heteropolyacids, for example aqueous H₃ [P(W₃O₁₀)_(4]). Acidic diatomaceous earth, acidic resins, such as DOWEX® 50[origin: Dow Chemical Co. (USA)] or Amberlyst IR-15, or an acidicaluminum oxide can also be used. Amongst the protonic acids, one can yetcite the hydrohalide acids such as hydrogen chloride, hydrogen bromideor hydrogen iodide.

As an active organic acid, trifluoroacetic or acetic acid can be used,in particular, one can also use a mixture of acetic and sulphuric acids,or methanesulphonic acid. Finally, as cited above, Lewis acids can beemployed. Particular examples of the latter are trifluoroboroetherate,tin chloride or titanium tetrachloride.

According to a preferred embodiment of the invention, the cyclizationreaction takes place in an inert organic solvent. To this end, it can becarried out in a solvent chosen from hydrocarbons such as petroleumether, halogenated hydrocarbons such as chloroform, methylene chlorideor trichloroethane, aromatic hydrocarbons, for example benzene, toluene,chlorobenzene or methoxybenzene, ethers such as dimethyl ether, esterssuch as ethyl acetate, or nitrogen containing hydrocarbons, for instancenitromethane, nitroethane or nitroisopropane. Finally, solvents such ascarbon disulphide or acetonitrile can also be used.

The results obtained with the different cited acidic reagents and thevarious solvents mentioned above, although perfectly reproducible, varyas a function of the operator's particular choice when using the processaccording to the invention. The same can be said as regards thetemperature used. The cyclization may, in fact, be carried out at atemperature ranging from -60° to +25°-30°. Obviously, the yields and theisomeric ratio of the compounds obtained varies in accordance with theoperator's choice. Preferred embodiments of this process are describedin the examples that follow. Any combination resulting from a specificchoice of acidic agent, solvent, temperature and, of course, startingproduct is dependent on the nature of the desired final products.

Separation of the products obtained can be easily achieved by simpledistillation.

Owing to its easy operation, the process of the invention presents amajor industrial interest. It is in fact an economical process whichallows the large scale production of polycyclic ethers which were untilnow of difficult access via the traditional synthetic methods.

The process of the invention is based on a novel type of cyclization.Indeed, the cyclization of a polyene of the type mentioned above havinga free or protected hydroxyl group at the end of a chain has neverbefore been reported, or even suggested, in the art. On the other hand,one of the major aspects of this type of cyclization should be pointedout: it is a perfectly stereospecific reaction. This characteristic ofthe process of the invention makes it possible to obtain polycyclicethers (I) in one or the other of the desired isomeric forms, as afunction of the structure and configuration of the chosen startingmaterial. This unexpected result is of major importance insofar as theproperties of the obtained ether, and namely their organolepticproperties, have a marked dependence on their molecular configuration.

More particularly, the process of the invention provides an isomericmixture having a preponderant content in isomer3aα,5aβ,9aα,9bβ-dodecahydro-3a,6,6,9a-tetramethyl-naphtho[2,1-b]furan.In addition, in the case of the cyclization of4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-hexen-1-ol leading toAMBROX, this reaction leads to preferential formation of trans-decalincompounds. In all the experiments carried out, the proportion ofcis-decalin compounds was never above 15% of the total weight of themixture. Now, such isomeric mixtures, whose composition is novel,possess in fact the more pronounced odor properties and constitutetherefore choice perfuming ingredients for the perfumer's creativeactivity.

The same preponderance of trans decalin compounds was also observed inthe cyclization of other compounds (IIa), as it will become apparentfrom the examples presented further on.

Although the process of the invention finds a particular application forthe preparation of AMBROX, its use does in fact allow the preparation ofvaried polycyclic ethers useful in perfumery and it represents thereforea general method, the use of which can bring an original solution to thesynthesis of odoriferous compounds, whether known or with newstructures. Amongst those whose structure is known, apart from AMBROX,one can cite the bicyclic ether of formula ##STR15## a compound ofnatural origin appearing in ambergris [Int. Congr. Essent. Oils, 7th,Kyoto, Oct. 7-11, 1977, p. 479; Helv. Chim. Acta 1976, 59, 1140-57], aswell as its higher homolog of formula ##STR16## or1,7,7-trimethyl-2-oxabicyclo[4.4.0]decane described by G. Ohloff et al.[Helv. Chim. Acta 1976, 59, 1140-57].

Concerning the starting products of formula (II), there are some whichhave already been described in the scientific literature. Such is thecase for 4,8,12-trimethyl-3,7,11-tridecenol or (E,E)-homofarnesol, forhomogeraniol or for4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-hexen-1-ol, disclosedrespectively in Bull. Soc. Chim. France 1960, 1072 and Tetrah. Letters1988, 29, 2401.

The compounds of formula (IIa) can be obtained, for example, fromaldehydes of formula ##STR17## which are either available on the marketor can be synthesized from known compounds.

Scheme I illustrates said process for preparing compounds (IIa) fromsaid aldehydes (n=0 in formula IIa): ##STR18## (a) addition reaction ofalkyl dialkylphosphonoacetate (ex.: methyl dimethylphosphonoacetate)according to Horner-Emmons [see Chem. Rev. 1974, 74, 87]

Examples of compounds prepared by this method include (E)- and(Z)-4-methyl-6-[2,6,6-trimethyl-1(2)-cyclohexen-1-yl]-3-hexen-1-ol and(E)- and(Z)-4-methyl-6-(2-methylene-6,6-dimethyl-1-cyclohexyl)-3-hexen-1-ol,defined by the following formulae: ##STR19##

As a reducing agent in step (a) of the above-mentioned process, ametallic reducing agent can be used, such as lithium aluminium hydride,sodium diethyl aluminium hydride (OMH) or yet Vitride.

Other methods for preparing compounds (IIa) can be used and aredescribed in detail in the examples presented hereinafter.

Particular cases of preparation of compounds (IIa) are given in thefollowing examples, wherein the temperatures are indicated in degreescentigrade and the abbreviations have the usual meaning in the art.

EXAMPLE 1 Acid cyclization of (E)- and(Z)-4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-hexen-1-ol, (E)-and (Z)-4-methyl-6-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-hexen-1-ol and(E)- and(Z)-4-methyl-6-(2-methylene-6,6-dimethyl-1-cyclohexyl)-3-hexen-1-ol

The cyclization of the first above-mentioned compound was carried outunder the reaction conditions described hereinafter. A series ofexperiments was run while keeping the nature and concentration of theacidic agent constant. To this end, 98% sulphuric acid was used in a 1:1proportion of acid relative to the starting product.

In most of the experiments carried out, 2.4 g of starting product wereused and said product was dissolved in 30 ml of solvent. One singleexception was that, when using nitroethane, a smaller amount of solventwas taken. Generally, the temperature was maintained at -50°, except inthe cases where the solvent solidified at this temperature or when theconversion rate was found to be bad.

The results obtained are summarized in the following table: ##STR20##

                                      TABLE                                       __________________________________________________________________________    Exper-                                                                        iment           Temp.                                                                              Products/Yields (%)                                      no  Solvent     [°C.]                                                                       a    b c   Isomer                                        __________________________________________________________________________    1   CH.sub.2 Cl.sub.2                                                                         -50  23    5                                                                              5   (E) 97% pure                                  2   CH.sub.2 Cl.sub.2                                                                         -50   4   31                                                                              9   (Z) 90% pure                                  3   CH.sub.2 Cl.sub.2                                                                         -50  24   19                                                                              7   mixture (E)/(Z) 2:1                           4   CH.sub.2 Cl.sub.2                                                                         -50  22   18                                                                              7   "                                             5   CH.sub.2 Cl.sub.2                                                                         -20  18   18                                                                              8   "                                             6   CH.sub.2 Cl.sub.2                                                                           0   5   16                                                                              9   "                                             7   CHCl.sub.3  -50  10   15                                                                              5   "                                             8   CH.sub.3 CCl.sub.3                                                                        -35   2    2                                                                              2   "                                             9   toluene     -50   5    6                                                                              3   "                                             10  toluene/NMP -50  12   12                                                                              5   "                                             11  chlorobenzene                                                                             -40   7    5                                                                              3   "                                             12  anisole     -20   7    4                                                                              4   "                                             13  acetonitrile                                                                              -50 t.a.                                                                            1    2                                                                              --  "                                             14  CS.sub.2    -40 -20                                                                             4    5                                                                              4   "                                             15  THF         -50 t.a.                                                                           --   --                                                                              --  "                                             16  petroleum ether                                                                           -50   2    2                                                                              2   "                                             17  petroleum ether/MeOH                                                                      -50 t.a.                                                                           --    4                                                                              2   "                                             18  MeNO.sub.2 /CH.sub.2 Cl.sub.2                                                             -30  12   16                                                                              5   "                                             19  nitroethane -50 -40                                                                            14   20                                                                              5   "                                             20  nitroethane -50 -20                                                                            17   23                                                                              6   "                                             21  nitro-isopropane                                                                          -50 -20                                                                            11   13                                                                              5   "                                             __________________________________________________________________________

In all of the experiments mentioned above, the reaction was carried outas follows. A solution of the starting alcohol (2.4 g; 8.9 mmol) in 5 mlof solvent was added dropwise over 15 min to a stirred mixture of 98%sulphuric acid (2.4 g; 24 mmol) in 25 ml of solvent at -50° and underN₂. After 3 h at -50°, the mixture was neutralized by pouring it into a10% aqueous solution of NaHCO₃. Extraction with ether, followed by theusual separation, neutralization, drying and evaporation treatments,yielded a residue which, once distilled, provided the desired products.Analysis of the distillate was carried out by gas chromatography on aCARBOWAX® column (10 m, capillary): 130°-170°/4° per min.

Another series of essays was realized by varying the proportion of acid.To this end, the following method was used.

A solution of 2.4 g (8.9 mmol) of an isomer mixture E/Z (2:1) ofstarting alcohol in 5 ml of CH₂ Cl₂ was added dropwise over 15 min to amixture of the acid in 25 ml of CH₂ Cl₂ at -50° under N₂. The reactionmixture was then treated as described before. The results obtained aresummarized in the following table.

                  TABLE                                                           ______________________________________                                        Exper-                                                                        iment             Amount of acid                                                                            Products/Yields (%)                             no    Acid        [g]         a      b   c                                    ______________________________________                                        22    H.sub.2 SO.sub.4                                                                          1,2          6      4  2                                    23    H.sub.2 SO.sub.4                                                                          2,4         24     19  7                                    24    H.sub.2 SO.sub.4                                                                          3,6         24     18  5                                    25    H.sub.2 SO.sub.4                                                                          4,8         27     23  10                                   26    H.sub.2 SO.sub.4                                                                          4,8         12     21  9                                    27    H.sub.2 SO.sub.4                                                                          7,2         19     20  8                                    28    H.sub.2 SO.sub.4                                                                          9,6          5     21  5                                    29    H.sub.2 SO.sub.4 /oleum*                                                                  2,6         22     17  6                                    30    oleum       2,4         18     14  5                                    31    oleum       4,8         18     15  5                                    ______________________________________                                         *10:1                                                                    

Finally, a series of experiments was carried out in order to examine theinfluence of the proportion of acid used and of the temperature on thecyclization yield and on the nature of the isomers obtained. The ensuingresults are summarized in the following table. The operating manner isdescribed hereinafter.

A 30% solution of the starting alcohol, isomeric mixture E/Z 2:1 (2.4 g;8.9 mmol) in the chosen solvent was added dropwise over 30 min to astirred mixture of 98% H₂ SO₄. After a reaction time of 30 min to 1 h,during which the reaction mixture was stirred at the temperatureindicated in the table, the mixture underwent the usual treatmentsalready described in the preceding experiments. The results obtained aresummarized in the following table.

                  TABLE                                                           ______________________________________                                        Exper-                           Products/Yields                              iment Solvent    H.sub.2 SO.sub.4                                                                      Temp.   (%)                                          no    [ml]       [g]     [°C.]                                                                          a   b       c                                ______________________________________                                        32    EtNO.sub.2 (10)                                                                          2,4     -60/-20 17  23      6                                33    EtNO.sub.2 (10)                                                                          4,8     -60/-40 22  31      7                                34    EtNO.sub.2 (220)                                                                         108     -60/-40 22  33      8                                35    EtNO.sub.2 (340)                                                                         108     -60/-40 23  36      7                                36    EtNO.sub.2 (30)                                                                          4,8       0      5  20      9                                37    EtNO.sub.2 (30)                                                                          7,2     -60     32  .sup.  29.sup.1)                                                                      4                                38    EtNO.sub.2 (30)                                                                          7,2     -60      1  .sup.  68.sup.2)                                                                      9                                39    n-PrNO.sub.2 (30)                                                                        4,8     -40     21  28      6                                40    n-PrNO.sub.2 (30)                                                                        7,2     -60     22  34      6                                41    i-PrNO.sub.2 (30)                                                                        2,4     -50/20  11  13      5                                42    i-PrNO.sub.2 (30)                                                                        7,2     -60     19  36      6                                ______________________________________                                         .sup.1) pure alcohol (E) (97%)                                                .sup.2) pure alcohol (Z) (90%)                                           

In the majority of the examined reaction conditions, the formation oftransdecalin isomers is greatly favored relative to that of theircorresponding cis isomers.

The cyclization of4-methyl-6-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-hexen-1-ol (alcohol A),in its isomeric forms (E)- and (Z)-, was carried out on 100 mg ofstarting alcohol in an excess of 98% sulphuric acid (5 mol equiv.) indichloromethane, at -50° and for 3 h. The reaction mixture was treatedin the usual manner described in the above-mentioned experiments.

The same applied to the cyclization of (E)- and(Z)-4-methyl-6-(2-methylene-6,6-dimethyl-1-cyclohexyl)-3-hexen-1-ol(alcohol B).

The following table summarizes the results obtained: ##STR21##

                  TABLE                                                           ______________________________________                                                  Products/Yields (%)                                                 Alcohol           a     b                                                     ______________________________________                                        (E)-A             19     5                                                    (Z)-A             2     27                                                    (E)-B            25      6                                                    (Z)-B             3     37                                                    ______________________________________                                    

The alcohols used as starting products in the process described abovecan be prepared according to the following method.

36 g (0.2 mol) of 30% sodium methylate in methanol were introduceddropwise, under vigorous stirring and N₂ atmosphere, into a mixturecontaining 41.2 g (0.2 mol) of2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-al and 40 g(0.22 mol) of methyl dimethylphosphonate. The reaction was exothermic.After the introduction, the mixture was kept at reflux for 1 h. Aftercooling, 30 ml of water were added and the mixture was extracted withpetroleum ether. The organic phase was separated and then washed toneutrality, dried and concentrated.

Distillation on a 10 cm length Vigreux column provided 48.2 g of methyl4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-hexadienoate. B.p.102°/4 Pa; yield 91.5%.

2-Methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-al is acommercial product (origin: L. Givaudan).

The ester obtained above was then reduced by means of lithium aluminumhydride according to the following method.

42.8 g (0.163 mol) of methyl4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-hexadienoate dilutedwith an equal volume of THF were added dropwise to a suspension of 6.2 g(0.163 mol) of LiAlH₄ in 500 ml of anhydrous THF, under nitrogen. Thereaction was exothermic and was kept below 30° by cooling with an icywater bath. The mixture was then heated to reflux during 5 h, thencooled to 10° and, at same temperature, there were added slowly,dropwise, 6.2 ml of water, 6.2 ml of 2N NaOH and finally 18.6 ml ofwater. The mixture was stirred for yet 5 min and a white precipitateformed, which was then filtered. After concentrating, the clear filtratewas distilled on a 10 cm length Vigreux column under a pressure of 3 Pa.The desired alcohols were thus obtained, in the form of an isomericmixture (E)/(Z); B.p. 76°/3 Pa; yield 85%.

IR: 3300 cm⁻¹

isomer (E):

IR: 3310, 1462, 1378, 1356, 1200, 1040, 870 cm⁻¹

¹ H-NMR: 1.00(6H,s); 1.41(2H,m); 1.58(2H,m); 1.61(3H,s); 1.70(3H,s);1.91(2H,t,J=6.5 Hz); 2.06(4H,s); 2.30(2H,q,J=7 Hz); 3.63(2H,t,J=7 Hz);5.16(1H,t,J=7 Hz) δ ppm

MS: M⁺ =236; m/e: 137(77), 121(11), 107(15), 95(100), 81(83), 69(32),55(35)

isomer (Z): B.p. 105°-110°/1 Pa

IR: 3320, 1470, 1442, 1370, 1358, 1200, 1040, 870, 824 cm⁻¹

¹ H-NMR: 1.02(6H,s); 1.22(2H,m); 1.37(2H,m); 1.64(3H,s); 1.78(3H,s);1.91(2H,t,J=6 Hz); 2.06(4H,m); 2.31(2H,q,J=7 Hz); 3.63(2H,t,J=6 Hz);5.11(1H,t,J=7 Hz) δ ppm

MS: M⁺ =236; m/e: 137(100), 121(9), 107(12), 95(81), 81(51), 69(19)

The isomeric alcohols derived from2-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-al and from2-methyl-4-(2-methylene-6,6-dimethyl-1-cyclohexyl)-2-buten-1-al wereprepared in an analogous manner. These aldehydes can be preparedaccording to the methods described by K.-H. Schulte-Elte et al. [Nouv.J. Chim. 1978, 2, 427-30] and I. M. Heilborn et al. [J. Chem. Soc. 1942,727], respectively.

4-methyl-6-(2,6,6-trimethyl-2-cyclohex-1-yl)-3-hexen-1-ol

isomer (E): B.p. 160°-170°/2 Pa

IR: 3300, 2900, 1440, 1380, 1360, 1040, 812 cm⁻¹

¹ H-NMR: 0.87(3H,s); 0.92(3H,s); 1.12(1H,m); 1.30-1.65(4H); 1.65(3H,s);1.68(3H,s); 1.96(2H,m); 2.05(2H,m); 2.28(2H,q,J=7 Hz); 3.61(2H,t, J=7Hz); 5.13(1H,t,J=7 Hz); 5.28(1H,s) δ ppm

MS: M⁺ =236; m/e: 136(74), 121(56), 109(41), 95(26), 81(100), 69(26),55(31), 41(64)

isomer (Z): B.p. 160°-170°/2 Pa

IR: 3320, 2900, 1442, 1380, 1360, 1042, 760 cm⁻¹

¹ H-NMR: 0.88(3H,s); 0.96(3H,s); 1.14(1H,m); 1.30-1.60(4H); 1.71(3H,s);1.74(3H,s); 1.96(2H,m); 2.07(2H,m); 2.28(2H,q,J=7 Hz); 3.62(2H,t, J=7Hz); 5.09(1H,t,J=7 Hz); 5.31(1H,s) δ ppm

MS: M⁺ =236; m/e: 136(38), 121(31), 109(42), 95(21), 81(100), 69(25),55(21), 41(62)

4-methyl-6-(2-methylene-6,6-dimethyl-1-cyclohexyl)-3-hexen-1-ol

isomer (E): B.p. 160°-170°/2 Pa

IR: 3300, 2900, 1640, 1440, 1380, 1360, 1042, 884, 630 cm⁻¹

¹ H-NMR: 0.84(3H,s); 0.92(3H,s); 1.21(1H,m); 1.35-1.85(7H); 1.64(3H,s);1.92-2.12(3H); 2.29(2H,q,J=7 Hz); 3.62(2H,t,J=7 Hz); 4.54(1H,s);4.76(1H,s); 5.12(1H,t,J=7 Hz) δ ppm

MS: M⁺ =236; m/e: 221(25), 177(25), 121(26), 109(61), 95(38), 81(84),69(61), 55(41), 41(100)

isomer (Z): B.p. 160°-170°/2 Pa

IR: 3300, 2900, 1640, 1440, 1380, 1362, 1042, 884, 630 cm⁻¹

¹ H-NMR: 0.83(3H,s); 0.92(3H,s); 1.22(1H,m); 1.34-1.70(6H); 1.73(3H,s);1.80-2.15(4H); 2.25(2H,m); 3.60(2H,t,J=7 Hz); 4.58(1H,s); 4.79(1H,s);5.11(1H,t,J=7 Hz) δ ppm

MS: M⁺ =236; m/e: 221(25), 177(27), 121(29), 109(70), 95(42), 81(90),69(60), 55(47), 41(100)

EXAMPLE 2 Acid cyclization of (E)- and(Z)-4,8-dimethyl-3,7-nonadien-1-ol (homogeraniol and homonerol)

The cyclization of homogeraniol and homonerol was carried out accordingto the method described in Example 1, by means of sulphuric acid inmethylene chloride at -50°. 1,6,6-Trimethyl-2-oxabicyclo[4.3.0]nonanewas thus obtained, with the cis/trans isomeric content indicated in thefollowing table:

    ______________________________________                                                              Final product                                                                             Isomeric ratio                              Experiment                                                                             Starting product                                                                           yield (%)   cis/trans                                   ______________________________________                                        1        (E)-         56          1:5                                         2        (Z)-         50          6:1                                         ______________________________________                                    

The starting products used in the above-described cyclization wereprepared by reduction, by means of LiAlH₄, of methyl4,8-dimethyl-3,7-nonadienoate following the method indicated in Example1.

The analytical characteristics of the two alcohols obtained were asfollows:

isomer (E):

IR: 3320, 2910, 1440, 1380, 1040, 880, 830 cm⁻¹

¹ H-NMR: 1.61(3H,s); 1.65(3H,s); 1.69(3H,s); 2.07(4H); 2.28(2H,dt,J=7.7Hz); 3.60(2H,t,J=7 Hz); 5.08(1H,t,J=7 Hz); 5.12(1H,t,J=7 Hz) δ ppm

MS: M⁺ =168; m/e: 125(22), 81(14), 69(100), 53(12), 41(96)

isomer (Z):

IR: 3320, 2900, 1440, 1380, 1040, 878, 830 cm⁻¹

¹ H-NMR: 162(3H,s); 1.69(3H,s); 1.73(3H,s); 2.08(4H); 2.28(2H,dt,J=7,7Hz); 3.60(2H,t,J=7 Hz); 5.12(1H,m); 5.14(1H,t,J=7 Hz) δ ppm

MS: M⁺ =168; m/e: 125(22), 81(12), 69(100), 53(13), 41(98)

EXAMPLE 3 Acid cyclization of (E)- and(Z)-4-methyl-6-(2,5,6,6-tetramethyl-2-cyclohexen-1-yl)-3-hexen-1-ol

The reaction was carried out following the process described in Example1 by means of 98% sulphuric acid and at -60°. To this end, 0.7 g ofstarting (E)-alcohol were treated with 1.4 g of H₂ SO₄ in 5 ml ofnitroethane. After stirring for 1 h at -60°, the reaction mixture waspoured on ice and the whole extracted with ether. After the usualneutralization and concentration treatments, a bulb-to-bulb distillationof the product was carried out at a temperature of 150°/20 Pa. 0.45 g ofmethyl-AMBROX were thus obtained, in the form of an isomeric mixturehaving the following main components:

3aα,5aα,7α,9aα,9bβ-dodecahydro-3a,6,6,7,9a-pentamethyl-naphtho[2,1-b]furan:

¹ H-NMR: 0.84(3H,d,J=7 Hz); 0.97(3H,s); 0.98(3H,s); 1.05(3H,s);1.14(3H,s); 3.85(2H,m) δ ppm

MS: M⁺ =250; m/e: 235(100), 151(29), 137(25), 123(30), 109(30), 97(77),83(36), 67(33), 55(52), 43(55)

3aβ,5aα,7α,9aα,9bβ-dodecahydro-3a,6,6,7,9a-pentamethyl-naphtho[2,1-b]furan:

¹ H-NMR: 0.79(3H,d,J=7 Hz); 0.92(3H,s); 0.98(3H,s); 1.09(3H,s);1.35(3H,s); 3.76(2H,m) δ ppm

MS: M⁺ =250; m/e: 2.35(100), 151(27), 137(28), 123(31), 109(31), 97(89),81(42), 67(37), 55(50), 43(76)

3aβ5aα,7α,9aα,9bα-dodecahydro-3a,6,6,7,9a-pentamethyl-naphtho[2,1-b]furan:

¹ H-NMR: 0.81(3H,d,J=7 Hz); 0.93(3H,s); 1.04(3H,s); 1.14(3H,s);1.15(3H,s); 3.85(2H,m) δ ppm

MS: M⁺ =250; m/e: 235(88), 151(22), 137(21), 121(25), 109(29), 97(100),81(26), 67(30), 55(42), 43(42)

3aα,5aα,7α,9aα,9bα-dodecahydro-3a,6,6,7,9a-pentamethyl-naphtho[2,1-b]furan:

¹ H-NMR: 0.76(3H,d,J=7 Hz); 0.94(3H,s); 0.98(3H,s); 1.02(3H,s);1.055(3H,s); 3.77(2H,m) δ ppm

MS: M⁺ =250; m/e: 235(89), 151(17), 135(14), 121(21), 109(26), 97(100),81(41), 69(34), 55(43), 43(47)

Following the same process, the cyclization of the (Z)- alcohol wascarried out, leading to methyl-AMBROX in the form of an isomeric mixturehaving the following main compounds:

3aα,5aβ,7α,9aα,9bβ-dodecahydro-3a,6,6,7,9a-pentamethyl-naphtho[2,1-b]furan:

¹ H-NMR: 0.67(3H,s); 0.81(3H,s); 0.845(3H,d,J=7 Hz); 0.90(3H,s);1.09(3H,s); 3.86(2H,m) δ ppm

MS: M⁺ =250; m/e: 235(100), 151(33), 137(42), 109(20), 97(47), 81(13),67(14), 55(16), 43(21)

3aα,5aβ,7α,9bα-dodecahydro-3a,6,6,7,9a-pentamethyl-naphtho[2,1-b]furan:

¹ H-NMR: 0.66(3H,s); 0.84(3H,d,J=7 Hz); 0.91(3H,s); 1.07(3H,s);1.37(3H,s); 3.81(2H,m) δ ppm

MS: M⁺ =250; m/e: 234(47), 151(100), 137(53), 123(17), 109(22), 95(27),81(17), 67(17), 55(17), 43(25)

These various isomers were separated by gas chromatography.4-Methyl-6-(2,5,6,6-tetramethyl-2-cyclohexen-1-yl)-3-hexen-1-ol, used asstarting product in the process described above, can be prepared from2-methyl-4-(2,5,6,6-tetramethyl-2-cyclohexen-1-yl)-2-buten-1-alfollowing the method described in the preceding examples. The citedaldehyde was prepared from cis- and trans-irone, according to thefollowing procedure.

5 g of trans-irone, 4 g of ethyl chloroacetate and 20 ml of absoluteether were treated under argon with potassium tert-butylate, preparedfrom 50 ml of tertbutanol and 4.3 g of potassium. The reaction was doneat room temperature. After leaving to react at this temperature for onenight, the reaction mixture was concentrated under vacuum and thenextracted with ether. The residue obtained was mixed with 10 ml of 10%soda and 30 ml of ethanol, and then maintained at reflux for 1 h. Afteracidification and extraction with ether, the organic extracts werecombined and, after the usual treatments, yielded, at b.p. 150°/10 Pa,2.7 g of the desired trans-aldehyde.

The cis-isomer of this same aldehyde was obtained following the samemethod as indicated above but starting from the irone ofcis-configuration. The various isomers of methyl-AMBROX, obtained asindicated above, are novel chemical entities possessing interestingorganoleptic properties, with an amber or woody-amber character, and cantherefore be used in perfumery.

EXAMPLE 4 Acid cyclization of (E)- and(Z)-1,4-dimethyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-hexen-1-ol

The reaction was carried out according to the process described inExample 1, by means of 95% sulphuric acid and at -20°. To this end, asolution of the above-mentioned alcohol (isomeric mixture E/Z 1.5:1, 4.2g, 0.017 mol) in CH₂ Cl₂ (10 ml) was treated with 4.3 g of H₂ SO₄ (0.042mol) in 40 ml of CH₂ Cl₂. After 3 h at -20°, the mixture was poured intocold saturated aqueous NaHCO₃ solution (100 ml). The phases wereseparated and the aqueous phase was extracted with Et₂ O (3×20 ml). Thecombined organic phase was dried (Na₂ SO₄), concentrated and theresidual oil distilled i.v. to afford a colorless oil (4.07 g) which waspurified by column chromatography [silica gel (350 g, toluene/ethylacetate 19:1, then ethyl acetate] to give a mixture of 12-methyl-AMBROXand 12-methyl-epi-AMBROX (2.92 g, yield 77%). The following tablesummarizes the results obtained in this experiment as well as thoseobtained in the similar cyclization of starting alcohols of (E)- or (Z)-configuration. ##STR22##

                  TABLE                                                           ______________________________________                                                  Products/Yields (%)                                                 Starting alcohol                                                                          a       b     c     d   cis-decalins                              ______________________________________                                        (E)-A       25      20     8     4  11                                        (Z)-A        2       2    26    23  12                                        (E/Z 1.5:1)-A                                                                             17      15    19    12  12                                        ______________________________________                                    

ANALYTICAL DATA2β,3aα,5aβ,9aα,9bβ-dodecahydro-2,3a,6,6,9a-pentamethyl-naphtho[2,1-b]furan

¹ H-NMR(360 MHz); 0.83(6H,2s); 0.88(3H,s); 1.11(3H,s); 1.19(3H,d,J=7Hz); 4.21(1H,m) δ ppm

MS: 250(0.5,M⁺), 235(100), 217(8), 151(10), 137(36), 111(52), 95(34),81(41)

b2α,3aα,5aβ,9aα,9bβ-dodecahydro-2,3a,6,6,9a-pentamethyl-naphtho[2,1-b]furan

¹ H-NMR(360 MHz): 0.83(3H,s); 0.85(3H,s); 0.87(3H,s); 1.14(3H,s);1.29(3H,d,J=7 Hz); 4.07(1H,m) δ ppm

MS: 250(3,M⁺), 235(100), 217(8), 151(18), 137(37), 111(56), 95(36)

c2α,3aα,5aβ,9aα,9bα-dodecahydro-2,3a,6,6,9a-pentamethyl-naphtho[2,1-b]furan

¹ H-NMR(360 MHz): 0.81(3H,s); 0.89(3H,s); 1.09(3H,s); 1.16(3H,d,J=7 Hz);1.37(3H,s); 4.11(1H,m) δ ppm

MS: 250(6,M⁺), 235(85), 151(30), 137(100), 111(57), 95(58 ), 81(60),43(98)

d2β,3aα,5aβ,9aα,9bα-dodecahydro-2,3a,6,6,9a-pentamethyl-naphtho[2,1-b]furan

¹ H-NMR(360 MHz): 0.81(3H,s); 0.89(3H,s); 1.09(3H,s); 1.26(3H,d,J=7 Hz);1.37(3H,s); 4.04(1H,m) δ ppm

MS: 250(8,M⁺), 235(46), 151(46), 137(95), 109(52), 95(48), 81(58),43(100)

The alcohols used as starting materials in the process described abovewere prepared from4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-hexen-1-ol (seeExample 1) following the method described [see Swern, J. Org. Chem. 43,2480 (1978)].

A solution of DMSO (2.2 g) in CH₂ Cl₂ (7 ml) was added within 5 min to astirred solution of oxalyl chloride (1.8 g, 14.2 mmol) in CH₂ Cl₂ (30ml) at -50°. After 3 min, a solution of4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-hexen-1-ol (E/Z 1.5:1;3 g, 12.7 mmol) in CH₂ Cl₂ (13 ml) was added within 5 min and themixture was allowed to stir at -50°→-30° during 2 h. Work-up waseffected by addition of (C₂ H₅)₃ N (6.5 g, 64.3 mmol) followed by anaqueous extraction with CH₂ Cl₂. The crude product, consisting of a1.5:1 E/Z mixture of corresponding aldehyde having the followinganalytical data, was used without purification in the next reactionstep.

isomer (E):

¹ H-NMR(360 MHz): 3.14(2H,d,J=7 Hz); 9.66(1H,m) δ ppm

MS: 234(6,M⁺), 201(7), 178(9), 160(11), 145(18), 137(27), 123(77),110(67), 95(99), 81(100)

isomer (Z):

¹ H-NMR(360 MHz): 3.16(2H,d,J=7 Hz); 9.66(1H,m) δ ppm

MS: 234(2,M⁺), 201(2), 160(2), 145(5), 137(81), 121(16), 109(11),95(100), 81(75)

The above-mentioned crude product was then dissolved in (C₂ H₅)₂ O (10ml) and the solution was added dropwise within 5 min to a freshlyprepared solution of CH₃ MgI (15 mmol) in (C₂ H₅)₂ 0 (30 ml) at 0°-10°.After 1 h at r.t., the mixture was poured onto cold 10% aqueous NH₄ Clsolution and extracted with ether. Work-up afforded the desired alcohols(E/Z 1.5:1) (2.2 g), readily separated by chromatography (silica gel).

(Z)-1,4-dimethyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-hexen-1-ol

R_(f) 0.25(toluene/ethyl acetate 9:1)

IR: 3530, 3390 (broad), 1434, 1360, 1340, 1240, 1100, 1050, 1030, 920cm⁻¹

¹ H-NMR(360 MHz,D₂ O): 1.02(6H,s); 1.20(3H,d,J=7 Hz); 1.42(2H,m);1.57(2H,m); 1.65(3H,s); 1.79(3H,s); 1.92(2H,t,J=7 Hz); 1.96-2.12(4H);2.18(2H,m); 3.79(1H,m); 5.14(1H,t,J=7 Hz) δ ppm

C-NMR: 139.6(s); 137.1(s); 127.3(s); 120.3(d); 68.0(d); 39.9(t);38.0(t); 35.0(s); 32.9(t); 32.8(t); 28.7(2q); 27.3(t); 23.5(q); 22.9(q);19.9(d); 19.6(t) δ ppm

MS: 250(0,M⁺), 137(95), 121(17), 107(18), 95(100), 81(74), 69(28)

(E)-1,4-dimethyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-hexen-1-ol

R_(f) 0.21 (toluene/ethyl acetate 9:1)

IR: 3540, 3390 (broad), 1440, 1370, 1350, 1250, 1110, 1036, 922 cm⁻¹

¹ H-NMR(360 MHz,D₂ O): 1.00(6H,s); 1.20(3H,d,J=7 Hz); 1.42(2H,m);1.57(2H,m); 1,61(3H,s); 1.69(3H,s); 1.91(2H,t,J=7 Hz); 2.07(4H,s);2.18(2H,m); 3.81(1H,m); 5.20(1H,t,J=7 Hz) δ ppm

C-NMR: 139.8(s); 137.1(s); 127.1(s); 119.4(d); 68.0(d); 40.5(t);39.9(t); 38.0(t); 35.0(s); 32.8(t); 28.7(2q); 28.0(t); 22.8(q); 19.8(q);19.6(t); 16.4(q) δ ppm

MS: 250(1,M⁺), 137(97), 121(19), 107(15), 95(100), 81(81), 69(25)

EXAMPLE 5 Acid cyclization of (E)- and(Z)-5-methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-hepten-1-ol

The reaction was carried out according to the process described inExample 1, using 95% sulphuric acid, at -20° under nitrogen. To thisend, a solution of (E)- or(Z)-5-methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-hepten-1-ol (2.1 g,8.1 mol) in CH₂ Cl₂ (5 ml) was treated with 2.1 g of H₂ SO₄ (0.02 mol)in 21 ml of CH₂ Cl₂. After 3 h stirring the mixture was poured into 10%aqueous NaHCO₃ solution (50 ml). Extraction (Et₂ O), work-up andbulb-to-bulb distillation i.v. afforded a pale yellow oil which waspurified by column chromatography [silica gel (370 g), cyclohexane/ethylacetate 7:3].

The product thus obtained contained several isomers of ambra oxide, ordodecahydro-4a,7,7,10a-tetramethyl-1H-naphtho[2,1-b]pyran, as well asuninteresting side products.

Amongst said isomers, the following structures were identified:##STR23##

Two other compounds, (a) and (c) diastereoisomers, were detected in weakamounts and their structure was not identified.

The following table summarizes the results obtained.

                  TABLE                                                           ______________________________________                                                   Products/Yields (%)                                                Starting alcohol                                                                           a     b         c   other isomers                                ______________________________________                                        (E)          3     16        2   3                                            (Z)          6     25        2   --                                           ______________________________________                                    

ANALYTICAL DATA4aα,6aβ,10aα,10bα-dodecahydro-4a,7,7,10a-tetramethyl-1H-naphtho[2,1-b]pyran

R_(f) (cyclohexane/ethyl acetate 7:3): 0.60

¹ H-NMR(360 MHz): 0.80(3H,s); 0.87(3H,s); 1.12(3H,s); 1.39(3H,s) δ ppm

MS: 250(15,M⁺), 235(55), 137(100), 111(92), 95(77), 81(76)

b4aα,6aβ,10aα,10bβ-dodecahydro-4a,7,7,10a-tetramethyl-1H-naphtho[2,1-b]pyran

M. p. 81°-83°

R_(f) (cyclohexane/ethyl acetate 19:1): 0.32

IR: 2920, 2850, 1446, 1380, 1364, 1120, 1078, 980 cm⁻¹

¹ H-NMR(360 MHz): 0.75(3H,s); 0.80(3H,s); 0.87(3H,s); 0.90-1.80 (16H);1.25(3H,s); 3.65(2H) δ ppm

¹³ C-NMR: 74.6(s); 60.8(t); 57.8(d); 56.4(d); 42.1(t); 42.0(t); 39.0(t);36.9(s); 33.3(q); 33.3(s); 27.7(t); 21.3(q); 19.9(q); 19.9(t); 18.6(t);18.1(t); 15.5(q) δ ppm

MS: 250(0.5,M⁺), 235(100), 137(32), 111(75), 95(43), 81(48), 69(40),55(46), 43(55)

c 4aα,6aβ,10bβ-dodecahydro-4a,7,7,10a-tetramethyl-1H-naphtho[2,1-b]pyran

R_(f) (cyclohexane/ethyl acetate 19:1): 0.32

MS: 250(1,M⁺), 235(100), 137(26), 121(27), 111(82), 95(42), 81(49)

The alcohols used as starting materials in the process described abovewere prepared by an alternative method to that represented in Scheme I,using conventional reactions. They were prepared from dihydro-β-ionone,as follows.

A solution of 4-(2,6,6-trimethyl-1-cyclohex-1-yl)-2-butanone (150 g,0.77 mol) in THF (500 ml) was added dropwise within 40 min to a stirredsolution of vinylmagnesium bromide [0.93 mol: freshly prepared from Mg(22,3 g, 0.93 mol) and vinyl bromide (100 g, 0.93 mol)] in THF (1 l) atreflux under N₂. After the addition the mixture was heated at refluxduring 1 h, cooled and then saturated aqueous NH₄ Cl solution (250 ml)and H₂ O (300 ml) were cautiously added dropwise. The phases wereseparated and the aqueous phase was extracted with Et₂ O. The combinedorganic phase was washed with H₂ O and saturated aqueous NaCl solution,dried (Na₂ SO₄), concentrated and fractionally distilled i.v. to afford3-methyl-5-(2,6,6-trimethyl-1-cyclohexyl)-1-penten-3-ol as a colorlessoil (151 g, 88%).

B. p. 85°-88°/20 Pa

R_(f) (toluene/ethyl acetate 19:1): 0.26

IR: 3410 (broad), 1475, 1456, 1410, 1360, 1104, 998, 910 cm⁻¹

¹ H-NMR(360 MHz,D₂ O): 0.98(6H,s); 1.31(3H,s); 1.41(2H,m); 1.58(3H,s);1.50-1.65(4H); 1.89(2H,t,J=6.5 Hz); 2.01(2H,m); 5.08(1H,d,J=11 Hz);5.23(1H,d,J=18 Hz); 5.95(1H,dd,J=18, 11 Hz) δ ppm

MS: 222(3,M⁺), 204(10), 189(31), 133(28), 121(54), 107(31), 95(100),81(56), 71(33), 55(39), 41(48)

The mixture of the alcohol prepared above (25 g, 0.104 mol), trimethylorthoacetate (72 g, 0.6 mol) and propionic acid (0.4 g, 5.4 mmol) washeated at reflux during 4 h whilst gradually increasing the externaloil-bath temperature (135°→150°) and continually distilling off (50 cmVigreux column) the volatile reaction components [MeOH+MeC(OMe)₃ ].After 4 h, the internal temperature was 116°-117° and the mixture wascooled to r.t. prior to the addition of a second portion of propionicacid (0.4 g). The mixture was now re-heated at reflux during 20 h(oil-bath temperature: 140°; internal temperature: 117°-119°) whilstagain continually removing the volatile components. The residual oil wasdistilled first at atmospheric pressure to remove excess MeC(OMe)₃(impure: 46 g, b.p. 108°-110°/9.8×10⁴ Pa) and then at 6.7 Pa to affordunreacted starting alcohol (4 g, i.e. 83% conversion) (B.p. 73°/6.7 Pa)and crude methyl5-methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-heptenoate (E/Z 1.3:1)as a colorless oil (23.5 g).

B. p. 110°-118°/6.7 Pa

IR: 2910, 1438, 1360, 1250, 1200, 1160, 986, 890 cm⁻¹

isomer (E) R_(f) (toluene): 0.31

¹ H-NMR(360 MHz): 0.99(6H,s); 1.42(2H,m); 1.55-1.65(2H); 1.60(3H,s);1.66(3H,s); 1.90(2H,t,J=7 Hz); 1.95-2.12(4H); 2.34(4H); 3.67(3H,s);5.12(1H,broad t,J=7 Hz) δ ppm

MS: 278(0.5,M⁺), 137(99), 121(13), 109(15), 95(100), 81(87), 67(26),55(21)

isomer (Z) R_(f) (toluene): 0.35

¹ H-NMR(360 MHz): 1.02(6H,s); 1.42(2H,m); 1.55-1.65(2H); 1.65(3H,s);1.74(3H,s); 1.92(2H,t,J=7 Hz); 1.95-2.12(4H); 2.34(4H); 3.67(3H,s);5.07(1H,broad t,J=7 Hz) δ ppm

MS: 278(1,M⁺), 137(96), 121(13), 109(12), 95(100), 81(87), 67(28),55(23)

A solution of the ester isomeric mixture obtained above (E/Z 1.3:1, 18g, 0.063 mol) in Et₂ O (100 ml) was added dropwise within 15 min to aslurry of LiAlH₄ (3.2 g, 0.084 mol) in Et₂ O (100 ml) at reflux underN₂. To the cooled mixture was then successively added H₂ O (3.2 ml), 20%aqueous NaOH solution (3.2 ml) and H₂ O (10 ml). Filtration (Hyflo),concentration of the filtrate and distillation i.v. affored5-methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-hepten-1-ol (E/Z 1.3:1)as a viscous colorless oil (15.5 g, yield 98%). B. p. 113°-123°/6.7 Pa.Column chromatography [silica gel (2×800 g), toluene/ethyl acetate 9:1]of 12 g afforded pure samples of (E)- and (Z)-heptenol.

(E)-5-methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-hepten-1-ol

IR: 3320(broad), 1440, 1380, 1360, 1200, 1060, 878 cm⁻¹

¹ H-NMR(360 MHz,D₂ O): 1.00(6H,s); 1.41(2H,m); 1.57(2H,m); 1.60(3H,s);1.63(2H,m); 1.66(3H,s); 1.91(2H,t,J=6 Hz); 1.97-2.13(6H); 3.65(2H,t,J=7Hz); 5.17(1H,t,J=7 Hz) δ ppm

¹³ C-NMR:137.2(s); 136.9(s); 127.0(s); 123.2(d); 62.7(t); 40.3(t);39.9(t); 35.0(s); 32.8(t); 28.7(2q); 28.0(t); 24.3(t); 19.8(q); 19.6(t);16.0(q) δ ppm

MS: 250(2,M⁺), 137(76), 121(25), 95(100), 81(74), 67(31), 55(30)

(Z)-5-methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-hepten-1-ol

IR: 3320(broad), 1448, 1380, 1360, 1200, 1060 cm⁻¹

¹ H-NMR(360 MHz, D₂ O): 1.02(6H,s); 1.42(2H,m); 1.57(2H,m); 1.62(2H,m);1.64(3H,s); 1.74(3H,d,J=1.5 Hz); 1.92(2H,broad t,J=6 Hz); 1.97-2.14(6H);3.64(2H,t,J=7 Hz); 5.12(1H,t,J=7 Hz) δ ppm

¹³ C-NMR: 137.2(s); 136.6(s); 127.1(s); 124.2(d); 62.6(t); 40.0(t);35.0(s); 33.2(t); 32.9(t); 32.7(2t); 28.7(2q); 27.4(t); 24.4(t);23.3(q); 19.9(q); 19,6(t) δ ppm

MS: 250(2,M⁺), 137(78), 121(23), 95(100), 81(81), 67(29), 55(30)

What we claim is:
 1. A process for the preparation of a polycyclic etherof formula ##STR24## wherein symbol R² represents a hydrogen atom or alower alkyl radical from C₁ to C₃, index n stands for integer 0 or 1 andsymbol R⁴ designates a hydrogen atom or a methyl radical, which processcomprises the cyclization by means of an acidic agent, in an inertorganic solvent, at a temperature of between -60° and +30° C., of anunsaturated compound of formula ##STR25## wherein symbols R² and R⁴ andindex n are defined as above, symbol R³ stands for a hydrogen atom or aprotecting group of the hydroxyl function bound to the oxygen atom andable to dissociate itself from the latter under the reaction conditionsand the wavy line represents a C--C bond of cis or trans configuration.